Most neurotrophins and Trk receptors are widely expressed not only in the nervous system but also in non-neuronal structures. However, very little is known about their functions outside the nervous system. Pharmacological intervention aimed at increasing or reducing neurotrophin signaling therefore has to take into account potential effects outside the targeted system. For example, a number of reports have implicated NGF in the development of the immune system and immune cell functions including inflammatory responses 6. Since mice with targeted deletion of neurotrophins or their Trk receptors die shortly after birth, these functions have not been thoroughly addressed in vivo. To generate a suitable animal model we have taken a novel approach of "reverse conditional gene targeting", in which TrkA is deleted only in non-neuronal cells (Coppola et al.. 2004) With this mutation we could show that the NGF receptor TrkA is not required for development of the immune system. However, TrkA deficiency causes defects associated with a specific class of B lymphocytes and immunoglobulin production as well as degranulation defects in mast cells. Thus, TrkA, appears to modulate functions of the immune system rather than its development. This was a striking result since many studies suggested that disruption of the NGF/TrkA system in the immune system would cause dramatic deficits. Currently, we are in the process of performing more functional studies in vivo using this reverse conditional TrkA mutant mouse model. For example, we have initiated an analysis of the degranulation potential of TrkA deficient mast cell. This is particularly important because there is evidence that NGF augments the allergic early-phase reaction in the lung and plasma and/or serum levels of NGF are increased in several allergic disorders including asthma, urticaria-angioedema, allergic rhinoconjuntivitisis and vernal keratoconjuntivitis. Since mast cells express exclusively TrkA, and not the p75 receptor, we are interested in analyzing whether the TrkA receptor may provide a target for the management of allergic disorders. Compounds blocking TrkA activity are already available but had not been vigorously pursued for in vivo applications because the literature had suggested severe immunological deficits in response. However, the relatively limited impact on immune system development reported by us indicates that TrkA could provide a useful target for the control of inflammatory diseases. Having validated the use of this new reverse conditional strategy to specifically restore a gene function in a specific organ, we plan to generate similar mouse mutants for both the TrkB and TrkC genes. These experiments should help elucidate the function of Trk genes in the non-neuronal compartments.